Department of Medicine, University of California, San Diego, La Jolla, California 92093-0663, USA.
J Biol Chem. 2012 Feb 3;287(6):4033-40. doi: 10.1074/jbc.M111.280065. Epub 2011 Dec 13.
ATG16L1 is an essential component of the autophagasome. The T300A allele of ATG16L1 is associated with the increased susceptibility to Crohn disease. In this study, we identified a novel function of ATG16L1, which suppresses signaling of the pro-inflammatory cytokine IL-1β. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1β signal transduction cascades. This amplification is due to elevated p62 levels in ATG16L1-deficient cells. We found that ATG16L1 regulates p62 levels via both autolysosomal and proteasomal pathways. For proteasomal degradation, we found that Cullin-3 (Cul-3) is a E3 ubiquitin ligase of p62 and that ATG16L1 is essential for neddylation of Cul-3, a step required for Cul-3 activation. Taken together our data indicate that loss-of-function of ATG16L1 results in a hyper-responsiveness to the IL-1β signaling because of the increased p62 level.
ATG16L1 是自噬体的一个必需组成部分。ATG16L1 的 T300A 等位基因与克罗恩病易感性增加有关。在这项研究中，我们发现了 ATG16L1 的一个新功能，它可以抑制促炎细胞因子 IL-1β 的信号转导。在小鼠胚胎成纤维细胞中缺失 ATG16L1 会显著放大 IL-1β 信号转导级联反应。这种放大是由于 ATG16L1 缺陷细胞中 p62 水平升高所致。我们发现 ATG16L1 通过自噬体和蛋白酶体途径来调节 p62 水平。对于蛋白酶体降解，我们发现 Cullin-3 (Cul-3) 是 p62 的 E3 泛素连接酶，并且 ATG16L1 对于 Cul-3 的 neddylation 是必需的，这是 Cul-3 激活所必需的步骤。总之，我们的数据表明，由于 p62 水平的增加，ATG16L1 的功能丧失会导致对 IL-1β 信号的过度反应。
